Common host proteins required for replication organelle function across coronaviruses

点击翻译按钮获取中文摘要

Coronaviruses are an important group of pathogens that infect both humans and livestock animals. Human coronaviruses mainly cause common cold-type illnesses and are responsible for approximately 10% of hospitalizations due to respiratory infections. In addition, an estimated 34 million working days were lost as a result of coughs and colds in 2016 meaning coronaviruses contribute to a major source of lost productivity. Coronaviruses are also responsible for economically important livestock diseases. The UK poultry industry contributes £3.4 billion annually to the economy and the most economically damaging infectious disease is caused by the coronavirus infectious bronchitis virus, with an estimated £23 million lost per year due to the disease. In pigs, an outbreak of another coronavirus, porcine epidemic diarrhoea virus, in the USA in 2013-2014 is estimated to have resulted in the death of 8 million pigs and is associated with estimated losses of $900 million - $1.8 billion across the whole economy. Finally, coronaviruses are able to jump between species resulting in new diseases, which are often highly pathogenic. This has happened twice since 2003 resulting in the emergence of SARS- and MERS-coronaviruses into the human population. There are currently no antiviral treatments available for coronaviruses and livestock industries require more effective vaccines that protect against multiple strains of virus. In order to develop new approaches to tackle coronaviruses, in particular ways to treat or prevent future, as yet unknown emerging coronaviruses, it is important to understand commonalities in how all coronaviruses behave and interact with their host cells.The synthesis of viral RNA is one stage of the coronavirus life cycle that is highly conserved and is critical for the propagation of new virus particles. This is required to direct the production of viral proteins that make up new particles and to produce copies of the viral genome to be packaged into new particles. Coronavirus RNA synthesis takes place at specialized sites called replication organelles (ROs). Our findings have shown that the appearance of ROs is conserved across all coronaviruses. However, little is known about how ROs form and which viral and cellular proteins are required. We propose that due to their central role in virus replication, and the fact that their appearance is highly conserved, all coronaviruses will hijack or use the same core set of host proteins to allow optimal RO assembly and function. An understanding of which cellular proteins all coronaviruses need to complete this critical stage of virus replication will underpin the development of universal anti-coronaviral drugs, development of vaccine viruses and even resistant livestock animals. In this project, we aim to identify and compare the viral and cellular proteins that are present in the ROs of a panel of five coronaviruses to identify the core set of host proteins required for this critical step of the coronavirus life cycle.